Cocaine dependence is a debilitating disease affecting millions of Americans and current treatment regimens are ineffective on nearly 90% of patients. Deficits in higher-order attention and memory processes (i.e., executive dysfunction, reduced working memory capacity and difficulties with attentional switching) are common amongst this group and likely contribute to relapse. However, even more basic deficits, including the failure to inhibit repeated sensory stimuli (i.e., sensory gating), are present. These gating deficits may be more severe in abusers with co-morbid psychiatric profiles such as a proneness to experience paranoia or users with more basic attentional disorders. Both of these sub-groups are associated with increased drug dependence and likelihood of relapse. A paradigm that is capable of identifying these sub-groups of users with associated co-morbidity issues would increase our knowledge on the neurobiology of addiction and could be used as a bio-marker for determining the efficacy of alternative treatment regimens, both of which are directly relevant to NIDA's overall mission statement. Therefore, we propose to use multimodal neuroimaging, including functional magnetic resonance imaging (FMRI), electroencephalography (EEG) and magnetoencephalography (MEG), and novel data fusion techniques to investigate basic inhibitory processes (i.e., sensory gating) in 12 healthy normal volunteers and 24 chronic cocaine abusers. Neuropsychological and psychological data will also be collected and correlated with performance on the gating task, with emphasis on clinical measures of attentional dysfunction and cocaine induced paranoia. The proposed task will be a variant of the traditional gating paradigm as participants will be exposed to pairs of identical tones and non-identical tones in addition to clicks. MEG and EEG data will be collected simultaneously, and FMRI data will be collected within 24 hours of the electrophysiological data. The specific aims of this project are 1) a more comprehensive understanding of the neurobiology of addiction by characterizing the neural networks (mesocorticolimbic pathway) underlying inhibitory processes to repeated and novel stimuli in chronic cocaine abusers, 2) to determine if basic failures in inhibition are indicative of faster relapse rates, and 3) to determine if basic inhibitory deficits are related to clinical characteristics (i.e., cocaine induced paranoia and attentional deficits) that are more prominent in certain sub-populations of abusers who might carry dual-diagnoses. This proposal is innovative and unique because it is one of the first attempts to utilize several different imaging modalities (FMRI/MEG/EEG) to investigate the neurobiology of addiction in a group where failures in inhibition have been shown to contribute to likelihood of relapse. Moreover, the use of multimodal neuroimaging and subsequent novel data fusion techniques will resolve a long-standing question in the gating literature, namely "where" and "when" the gating deficit occurs. Our long-term goal (planned R01 submission) is to evaluate the multi-modal imaging data as a predictor of treatment success, and to use task performance to identify a sub-group of patients where alternative treatment interventions should be considered. The minimal cognitive demands of this task also make it ideal for studying cocaine dependence in animals so that novel models of addiction can be developed and pharmacologically tested. Cocaine abuse continues to be a major health problem in the United States with approximately 1.8 million current users. Chronic cocaine abuse and dependence are associated with major medical, neurological, neuropsychiatric, social and interpersonal complications for the individual, their support network and society at whole. This grant will utilize neuroimaging techniques to increase our understanding of the neurobiology of addiction and to determine whether these techniques may be a more sensitive measure and predictor of relapse amongst certain sub-groups of cocaine users. [unreadable] [unreadable] [unreadable]